Effects of 2,2',4'‑trihydroxychalcone on the proliferation, metastasis and apoptosis of A549 human lung cancer cells

Sun,Jia-Lin; Cao,Zhan-Qi; Sun,Shi-Wei; Sun,Zhong-Hua; Sun,Shu-Hong; Ye,Jin-Feng; Leng,Ping

doi:10.3892/ol.2022.13236

Effects of 2,2',4'‑trihydroxychalcone on the proliferation, metastasis and apoptosis of A549 human lung cancer cells

Authors:
- Jia-Lin Sun
- Zhan-Qi Cao
- Shi-Wei Sun
- Zhong-Hua Sun
- Shu-Hong Sun
- Jin-Feng Ye
- Ping Leng
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Affiliations: Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China, Department of Natural Medicine and Pharmacognosy, School of Pharmacy, Qingdao University, Qingdao, Shandong 266071, P.R. China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266100, P.R. China
Published online on: February 9, 2022 https://doi.org/10.3892/ol.2022.13236
Article Number: 116
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to evaluate the antitumor effects of 2,2',4'‑trihydroxychalcone (7a) on the A549 human lung cancer cell line. A549 cells were treated with different concentrations of 7a for different time periods. Cells without 7a were used as the negative control group. Cell proliferation, invasion, vasculogenic mimicry (VM) formation, heterogeneous adhesion and apoptosis were measured using Cell Counting Kit‑8, Transwell invasion, VM, adhesion and flow cytometric assays, respectively. In addition, the expression of related proteins was determined using western blot analysis or ELISA. The present study found that 7a had a significant inhibitory effect on the survival rate of the A549 lung cancer cells but almost no effect on BEAS‑2B human lung epithelial cells or human venous endothelial cells. The migration rate, VM length, invasion rate and heterogeneous adhesion number of cells treated with 7a significantly decreased as the concentration increased, while the apoptosis rate increased. Western blot analysis showed that 7a treatment significantly increased the expression levels of E‑cadherin, cleaved poly (ADP‑ribose) polymerase, Bax and caspase‑3 and simultaneously decreased the expression levels of metalloproteinase‑2/9, Bcl‑2, phosphorylated (p)‑PI3K, p‑AKT, p‑mTOR, vascular endothelial growth factor (VEGF), E‑selectin and N‑cadherin. At the same time, the ELISA results showed that the level of the pro‑angiogenic factor VEGF in the culture media was reduced in the presence of 7a. In addition, 7a could also reduce the nuclear NF‑κB protein expression, which could inhibit the gene transcription of tumor apoptosis and metastasis‑related proteins. Therefore, 7a may exert inhibitory effects on A549 cells by inhibiting cell proliferation, migration, VM formation and heterogeneous adhesion, as well as by inducing apoptosis through the suppression of the PI3K/AKT/NF‑κB signaling pathway; these findings suggested that 7a may be a promising agent for the treatment of lung cancer.

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1	Molina JR, Yang P, Cassivi SD, Schild SE and Adjei AA: Non-small cell lung cancer: Epidemiology, risk factors, treatment and survivorship. Mayo Clin Proc. 83:584–594. 2008. View Article : Google Scholar : PubMed/NCBI
2	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
3	Quint LE, Tummala S, Brisson LJ, Francis IR, Krupnick AS, Kazerooni EA, Iannettoni MD, Whyte RI and Orringer MB: Distribution of distant metastases from newly diagnosed non-small cell lung cancer. Ann Thorac Surg. 62:246–250. 1996. View Article : Google Scholar : PubMed/NCBI
4	Vaya J, Belinky PA and Aviram M: Antioxidant constituents from licorice roots: Isolation, structure elucidation and antioxidative capacity toward LDL oxidation. Free Radic Biol Med. 23:302–313. 1997. View Article : Google Scholar : PubMed/NCBI
5	Chan SC, Chang YS, Wang JP, Chen SC and Kuo SC: Three new flavonoids and antiallergic, anti-inflammatory constituents from the heartwood of Dalbergia odorifera. Planta Med. 64:153–158. 1998. View Article : Google Scholar : PubMed/NCBI
6	Yamamoto S, Aizu E, Jiang H, Nakadate T, Kiyoto I, Wang JC and Kato R: The potent anti-tumor-promoting agent isoliquiritigenin. Carcinogenesis. 12:317–323. 1991. View Article : Google Scholar : PubMed/NCBI
7	Cuendet M, Guo J, Luo Y, Chen S, Oteham CP, Moon RC, van Breemen RB, Marler LE and Pezzuto JM: Cancer chemopreventive activity and metabolism of isoliquiritigenin, a compound found in licorice. Cancer Prev Res (Phila). 3:221–232. 2010. View Article : Google Scholar : PubMed/NCBI
8	Tian T, Sun J, Wang J, Liu Y and Liu H: Isoliquiritigenin inhibits cell proliferation and migration through the PI3K/AKT signaling pathway in A549 lung cancer cells. Oncol Lett. 16:6133–6139. 2018.PubMed/NCBI
9	Liang CC, Park AY and Guan JL: In vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc. 2:329–333. 2007. View Article : Google Scholar : PubMed/NCBI
10	Andrews N Yu LG, Zhao Q, McKean D, Williams JF, Connor LJ, Gerasimenko OV, Hilkens J, Hirabayashi J, Kasai K and Rhodes JM: Galectin-3 interaction with thomsen-friedenreich disaccharide on cancer-associated MUC1 causes increased cancer cell endothelial adhesion. J Biol Chem. 282:773–781. 2007. View Article : Google Scholar : PubMed/NCBI
11	Schmittgen TD and Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 3:1101–11108. 2008. View Article : Google Scholar : PubMed/NCBI
12	Herzig M, Savarese F, Novatchkova M, Semb H and Christofori G: Tumor progression induced by the loss of E-cadherin independent of beta-catenin/Tcf-mediated wnt signaling. Oncogene. 26:2290–2298. 2007. View Article : Google Scholar : PubMed/NCBI
13	Passalidou E, Trivella M, Singh N, Ferguson M, Hu J, Cesario A, Granone P, Nicholson AG, Goldstraw P, Ratcliffe C, et al: Vascular phenotype in angiogenic and non-angiogenic lung non-small cell carcinomas. Br J Cancer. 86:244–249. 2002. View Article : Google Scholar : PubMed/NCBI
14	Xu X, Zong Y, Gao Y, Sun X, Zhao H, Luo W and Jia S: VEGF induce vasculogenic mimicry of choroidal melanoma through the PI3k signal pathway. Biomed Res Int. 2019:39091022019. View Article : Google Scholar : PubMed/NCBI
15	Cao Z, Hao Z, Xin M, Yu L, Wang L, Zhang Y, Zhang X and Guo X: Endogenous and exogenous galectin-3 promote the adhesion of tumor cells with low expression of MUC1 to HUVECs through upregulation of N-cadherin and CD44. Lab Invest. 98:1642–1656. 2018. View Article : Google Scholar : PubMed/NCBI
16	Xu G, Zhang W, Bertram P, Zheng XF and McLeod H: Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common human tumors. Int J Oncol. 24:893–900. 2004.PubMed/NCBI
17	Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, Stein KD, Alteri R and Jemal A: Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 66:271–289. 2016. View Article : Google Scholar : PubMed/NCBI
18	Jung SK, Lee MH, Lim DY, Kim JE, Singh P, Lee SY, Jeong CH, Lim TG, Chen H, Chi YI, et al: Isoliquiritigenin induces apoptosis and inhibits xenograft tumor growth of human lung cancer cells by targeting both wild type and L858R/T790M mutant EGFR. J Biol Chem. 289:35839–35848. 2014. View Article : Google Scholar : PubMed/NCBI
19	Nakajima S, Doi R, Toyoda E, Tsuji S, Wada M, Koizumi M, Tulachan SS, Ito D, Kami K, Mori T, et al: N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res. 10:4125–4133. 2004. View Article : Google Scholar : PubMed/NCBI
20	Merchant N, Nagaraju GP, Rajitha B, Lammata S, Jella KK, Buchwald ZS, Lakka SS and Ali AN: Matrix metalloproteinases: Their functional role in lung cancer. Carcinogenesis. 38:766–780. 2017. View Article : Google Scholar : PubMed/NCBI
21	Brown GT and Murray GI: Current mechanistic insights into the roles of matrix metalloproteinases in tumour invasion and metastasis. J Pathol. 237:273–281. 2015. View Article : Google Scholar : PubMed/NCBI
22	Thi MU, Trocmé C, Montmasson MP, Fanchon E, Toussaint B and Tracqui P: Investigating metalloproteinases MMP-2 and MMP-9 mechanosensitivity to feedback loops involved in the regulation of in vitro angiogenesis by endogenous mechanical stresses. Acta Biotheor. 60:21–40. 2012. View Article : Google Scholar : PubMed/NCBI
23	Makrilia N, Kollias A, Manolopoulos L and Syrigos K: Cell adhesion molecules: Role and clinical significance in cancer. Cancer Invest. 27:1023–1037. 2009. View Article : Google Scholar : PubMed/NCBI
24	Zhao Q, Barclay M, Hilkens J, Guo X, Barrow H, Rhodes JM and Yu LG: Interaction between circulating galectin-3 and cancer-associated MUC1 enhances tumour cell homotypic aggregation and prevents anoikis. Mol Cancer. 9:1542010. View Article : Google Scholar : PubMed/NCBI
25	Zhao Q, Guo X, Nash GB, Stone PC, Hilkens J, Rhodes JM and Yu LG: Circulating galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface. Cancer Res. 69:6799–6806. 2009. View Article : Google Scholar : PubMed/NCBI
26	Popper HH: Progression and metastasis of lung cancer. Cancer Metastasis Rev. 35:75–91. 2016. View Article : Google Scholar : PubMed/NCBI
27	Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, Trent JM, Meltzer PS and Hendrix MJ: Vascular channel formation by human melanoma cells in vivo and in vitro: Vasculogenic mimicry. Am J Pathol. 155:739–752. 1999. View Article : Google Scholar : PubMed/NCBI
28	Shirakawa K, Tsuda H, Heike Y, Kato K, Asada R, Inomata M, Sasaki H, Kasumi F, Yoshimoto M, Iwanaga T, et al: Absence of endothelial cells, central necrosis and fibrosis are associated with aggressive inflammatory breast cancer. Cancer Res. 61:445–451. 2001.PubMed/NCBI
29	Sood AK, Seftor EA, Fletcher MS, Gardner LM, Heidger PM, Buller RE, Seftor RE and Hendrix MJ: Molecular determinants of ovarian cancer plasticity. Am J Pathol. 158:1279–1288. 2001. View Article : Google Scholar : PubMed/NCBI
30	Sharma N, Seftor RE, Seftor EA, Gruman LM, Heidger PM Jr, Cohen MB, Lubaroff DM and Hendrix MJ: Prostatic tumor cell plasticity involves cooperative interactions of distinct phenotypic subpopulations: Role in vasculogenic mimicry. Prostate. 50:189–201. 2002. View Article : Google Scholar : PubMed/NCBI
31	Mei J, Gao Y, Zhang L, Cai X, Qian Z, Huang H and Huang W: VEGF-siRNA silencing induces apoptosis, inhibits proliferation and suppresses vasculogenic mimicry in osteosarcoma in vitro. Exp Oncol. 30:29–34. 2008.PubMed/NCBI
32	Meier P, Finch A and Evan G: Apoptosis in development. Nature. 407:796–801. 2000. View Article : Google Scholar : PubMed/NCBI
33	Brown R: The bcl-2 family of proteins. Br Med Bull. 53:466–477. 1997. View Article : Google Scholar : PubMed/NCBI
34	Knight T, Luedtke D, Edwards H, Taub JW and Ge Y: A delicate balance-The BCL-2 family and its role in apoptosis, oncogenesis and cancer therapeutics. Biochem Pharmacol. 162:250–261. 2019. View Article : Google Scholar : PubMed/NCBI
35	Breckenridge DG and Xue D: Regulation of mitochondrial membrane permeabilization by BCL-2 family proteins and caspases. Curr Opin Cell Biol. 16:647–652. 2004. View Article : Google Scholar : PubMed/NCBI
36	Xia J, Dai L, Wang L and Zhu J: Ganoderic acid DM induces autophagic apoptosis in non-small cell lung cancer cells by inhibiting the PI3K/Akt/mTOR activity. Chem Biol Interact. 316:1089322020. View Article : Google Scholar : PubMed/NCBI
37	Zhang Z, Zhu J, Huang Y, Li W and Cheng H: MYO18B promotes hepatocellular carcinoma progression by activating PI3K/AKT/mTOR signaling pathway. Diagn Pathol. 13:852018. View Article : Google Scholar : PubMed/NCBI
38	Krencz I, Sztankovics D, Danko T, Sebestyen A and Khoor A: Progression and metastasis of small cell lung carcinoma: The role of the PI3K/Akt/mTOR pathway and metabolic alterations. Cancer Metastasis Rev. 27:doi: 10.1007/s10555-021-10012-4. 2021.PubMed/NCBI
39	Seo BR, Min KJ, Cho IJ, Kim SC and Kwon TK: Curcumin significantly enhances dual PI3K/Akt and mTOR inhibitor NVP-BEZ235-induced apoptosis in human renal carcinoma Caki cells through down-regulation of p53-dependent Bcl-2 expression and inhibition of Mcl-1 protein stability. PLoS One. 9:e955882014. View Article : Google Scholar : PubMed/NCBI
40	Chien CS, Shen KH, Huang JS, Ko SC and Shih YW: Antimetastatic potential of fisetin involves inactivation of the PI3K/Akt and JNK signaling pathways with downregulation of MMP-2/9 expressions in prostate cancer PC-3 cells. Mol Cell Biochem. 333:169–180. 2010. View Article : Google Scholar : PubMed/NCBI
41	Zhong XS, Zheng JZ, Reed E and Jiang BH: SU5416 inhibited VEGF and HIF-1alpha expression through the PI3K/AKT/p70S6K1 signaling pathway. Biochem Biophys Res Commun. 324:471–480. 2004. View Article : Google Scholar : PubMed/NCBI
42	Aggarwal BB: Nuclear factor-kappaB: The enemy within. Cancer Cell. 6:203–208. 2004. View Article : Google Scholar : PubMed/NCBI
43	Zhou P, Wang C, Hu Z, Chen W, Qi W and Li A: Genistein induces apoptosis of colon cancer cells by reversal of epithelial-to-mesenchymal via a Notch1/NF-κB/slug/E-cadherin pathway. BMC Cancer. 17:8132017. View Article : Google Scholar : PubMed/NCBI
44	Li J, Lau GKK, Chen L, Dong SS, Lan HY, Huang XR, Li Y, Luk JM, Yuan YF and Guan XY: Interleukin 17A promotes hepatocellular carcinoma metastasis via NF-κB induced matrix metalloproteinases 2 and 9 expression. PLoS One. 6:e218162011. View Article : Google Scholar : PubMed/NCBI
45	Shibata A, Nagaya T, Imai T, Funahashi H, Nakao A and Seo H: Inhibition of NF-kappaB activity decreases the VEGF mRNA expression in MDA-MB-231 breast cancer cells. Breast Cancer Res Treat. 73:237–243. 2002. View Article : Google Scholar : PubMed/NCBI